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Yi Zhang, Ph.D.
Functional Characterization of the Histone Demethylases
Histone methylation has attracted much attention due to its role in multiple biological processes including transcriptional regulation, epigenetic inheritance, and cancer. Recent studies indicate that, like other histone modifications, methylation can be actively reversed through demethylation. Histone demethylases identified so far include LSD1 and the JmjC domain-containing proteins. Given that changes in epigenetic modifications are usually associated with changes in transcription state or cell identities, histone demethylase activities must be tightly regulated. Modulation of histone demethylase activity can be achieved by the enzymes’ association with functional partners or through covalent modifications, particularly phosphorylation. Interestingly, our preliminary data suggest that many of the JmjC domain-containing histone demethylases are subject to phosphorylation. In this study, we plan to extend our observation to understand how phosphorylation of histone demethylases regulate their enzymatic activities. Toward this end, I propose to use an integrative approach to achieve the following
- Identification of the JmjC histone demethylases whose enzymatic activities are regulated by phosphorylation. This will be accomplished by in vivo labeling to determine which of the known histone demethylases are subject to phosphorylation. Then the role of phosphorylation on modulating the enzymatic activities will be tested by comparing the demethylase activity with or without the treatment with phosphatase.
- Identification of the phosphorylation site(s) as well as the responsible kinase(s). Mapping of the phosporylation site(s) can be achieved using a variety of approaches that include deletion, mutation followed by in vivo labeling, as well as mass spectrometry. After mapping of the phosphorylation site(s), the responsible kinase can be identified by either a consensus-based candidate approach or activity-based biochemical purification.
The proposed studies are expected to: 1) identify the histone demethylases whose activities are regulated by phosphorylation; 2) identify the responsible kinase and the phosphorylation site(s). This will set the stage for understanding how dynamic changes in histone methylation contributes to gene expression and cell fate determination.